Benzhydryl amino ethers



given above or as acid addition salts of the base per However, because of the high activity Federated ova l6, 1

BENZRYL AMINO ETHERS George Rieveschl, Jr Grosse Pointe Woods, Mich., aasignor to Parke, Davis & Company, Detroit, Mich.,a corporation ofMichigan No Drawing. Application June 2, 1947, Serial No. 751,983

8 Claims. louse-24s) l 2 The invention relates to amino ethers and their The free bases and the .acid addition salts of acid addition salts. This application is a conthe basically substituted benzhydryl ethers are, tinuation-in-part of my copending application, ln-addition to being useful as intermediates in Serial No. 531,639, filed April 18, 1944, now Patent the synthesis of other organic compounds, pow- No. 2,421,714, issued June 3, 1947, and relates to 5 erful antlspasmodicsend anti istami e e ts. basically substituted benzhydryl ethers and their As antispasmodics they are useful in preventing acid addition salts. The free bases of the basssmooth muscle spasms induced y histamine, ically substituted benzhydryl others of the invenacetyl choline or barium chlorid An e pr ption have the formula, erty of these compounds is that they inhibit gastrio secretion which has been induced either by meal or histamine stimulus. The new compounds Q may be administered to humans orally, paren- CE O C Earn terally, rectally or as a vapor or mist. They find particular use in humans for treatment of aller- J 31c conditions (asthma, urticaria, histamine a cephalagiaand anaphylactic shock) and smooth where a an integer or .2 to o inclusive, R is a muscle spasms (binary spasm and dysmenor piperldmo, morpholino, thiomorpholino or a pyrrhea-L example, the communal Shown in roildlno radical and R1 and Po are the same or Example 1] fiwmeridmoethm benzhydryl ether ff f' represent hydrogeninalogen' lower hydrochloride, may be administered to humans alizyl radicals or loxver allsoxy radicals. in a dosage of 100 to 8% mg. per day and The cicmpcunqs P 3- presen" mv?mmn may intravenously in a dosage of 100 to 600 mg. per be Obtained as was? hiwmg me formula day and intravenously in a dosage of 10 to 100 mg.

with inorganic or organic acids. dome examples of this compound and the other compounds of 0f the salts which may be Prepared by the meththis invention, it has been found that a dosage of ods hereinafter described are the hydrochloride, 150 per day Orally or 20 mg per day by the hydmbmmidev hydroiodide- Sulfate phosphate intravenous route is usually sufilcient in the acetate, citrate, oxalate, succinate, benzoate, treatment f smooth muscle spasms and most tartrate, phthalate, maleate, oleate and the like. allergic condmona The basically Substituted benZhF/dryl ether The invention is illustrated by'the following compounds of the invention may be prepared by examples; several different processes. For example, these compounds may be prepared by the condensation of a benzhydryl halide with an w-R-substituted Example 1.-B-Piperidinoeihyl benzhydryl ether aliphatic alcohol. The condensation of these two reactants may be carried out by several different 0130-0150391 methods, i. e. it may be efiected in the presence 013mg,

or absence of an acid-binding agent or with or without a solvent. Another method for prepar- 40 (a) 247 g. of benzhydryl bromide is added E inc these Compounds s ts in a ti anfilkali a refluxing solution of 260 g. of B-piperldinoethla Sa l/0f e y ol th & id-Su st tuted anol and 100 cc. of toluene. After the addition aliphatic halide or, if desired, the reactants may has been completed, the mixture is refluxed about be interchanged on an alkali metal salt of a w-R- fifteen hours, cooled and the lower layer consistsuostituted aliphatic alcohol reacted with a benz- 4-5 ing of the hydrobromide salt of B-plperidinoethhydryl halide. A further method of preparation anol drawn oil. The upper layer is distilled in consists in reacting an w-haloalkyl benzhydry vacuo to obtain the desired ,G-N-piperidinoethyl other with a piperidlne, morphollne, thiomorphobenzhydryl ether as a colorless liquid. line or pyrrolidine. Attention is directed to my The free base may also be purified through the copending applications, Serial Nos. 688320, acid oxalate acid addition salt. The excess amino 688,421, 688,422 and 688.423, all filed August 5, alcohol and toluene are distilled from the upper i946, and Serial No. 15,257, filed March 16, 1948, layer of the reaction mixture at atmospheric preswherein some of the novel features of several of sure or at slightly reduced pressure and the resithe above processes are more fully described and due added to a warm solution of 126 g. of oxalic claimed. I 5-) acid dihydrate in 500 cc. of isopropanol. The

crytalline acid oxalate salt which separates iron the solution is collected. treated with an excess or 25% potassium hydroxide solution. The free base of the product which separates as an oily layer from the alkaline solution in almost pure form is drawn oil and stored assuch or used in the preparation of an acid addition salt as described below. A

The free base is converted to the hydrochloride it in dry ethyl ether and addins an excess of dry gaseous hydroaen chloride gas. The precipitated salt is collected and purified by recrystallization from isopropanol; M. P. 168.5- 2.6 C. The hydrobromide salt may be preparfi in a similar manner and recrys irom either absolute ethanol-ether mixture or iso-.

panol. e (b) 18.4 g. of benxhydrol. 5g. 0! sodium and 120 g. of xylene are refluxed for ten hours. The solution is cooled and the excess sodium removed. An ether solution containing 18.4 g. of p-piperidinoethyl chloride is added and the mixture refiuxed for three hours. The mixture is and treated with water to dissolve the inorganic salts. The organic layer is separated. washed several-times with water and then extracted with several portions of 8 N hydrochloric acid. The acid extracts are treated with decolorizing carbon and filtered. The free base is liberated from the acid solution by the additionoi 20% sodium hydroxide solution, taken up in ether and the ether extract dried. the residue distilled under reduced pressure to obtain the pure free base of p-piperidinoethyl benzhydryl ether. The hydrochloride salt is prepared by dissolving the free base in anhydrous ether and slowly adding an alcoholic solution or en chloride. The salt is collected and purified by recrystallisation from isopropanol; M. P. 168-9 0.

[sample zp-lilorpholimcthyl benshydryl ether CHsOHs A mixture consisting of 524g. of p-morpholinoethanol and 65 g. of potassium carbonate is heated at 120 C. and 202.5 g. o! benshydrrl chloride added to the stirred mixture over a .period of one hour. After the addition has been completed the mixture is stirred and heated for an additional fiiteen hours and then the excess amino alcohol distilled-oi! in vacuo. The residue is washed with water to remove the potassium chloride and then added 126 g. of oxalic acid dlhydrate in 600 cc. of isopropanol. The acid oxalate salt of the desired product which separates on cooling is collected, suspended in water and treated with an excess oi 30% sodium hydroxide solution in the cold. The free base is extracted with ether, the ether extract dried and then treated with an excess of dry hydrogen chloride gas. The white hydrochloride of p-morpholinoethyl benxhydryl ether is collected and purified by recrystallization irom isopropanol; M. P. 182-8 C.

The citrate salt can be prepared by treating an ether solution of the tree base with, a saturated ether solution oicitric acid. The citrate which separates from the solution as a My divided powder is filtered c1! and purified by washing it with ether.

250 mg. per day of the compounded! this e!- The ether is distilled and.

suspended in water. and

k the amino alcohol. A solution the mixture is cooled e to a warm solution of I ample given solution of the free base the 4 orallyortbm-perdaybythe travenous route is an adequate dosage in treatment of smooth muscle spasms lergic conditions due to histamine.

trample H-Thiomorpholimethfll benshyd I other 1 the oi 294 g. 0! benshydryl iodide in 800 cc. oi. dry benzene is slowly to the rapidly stirred and refiuxing mixture and alter the addition has been completed refiuxed for fifteen hours. The mixture is cooled, washed with several of water to remove .the sodium iodide and the organic layer distilled in vacuo to remove the benzene and excess amino alcohol. The residue is treated with an excess of dilute hydrochloric acid and the mixture extracted with ether. The

discarded and the aqueous solution made alkaline with 20% sodium hydroxide solution in the cold. The free base is extracted with ether. the ether extract dried and treated with an excess of dry hydrogen bromide gas. The hydrobromide salt of the desired p-thiomorpholinoethyl benshydryl ether which separates is collected and purified by recrystallization from isopropanol.

The compound of proximately the same dosages as the compound of Example 2 in the treatment of smooth muscle spasms and allersic conditions due to histamine.

Example 4-s-Pyrroudionoethyl benshudryl an excess of dry gaseous hydrogen chloride gas.

The precipitated salt is collected and purified by recrystallization from isopropanol. By adding an equivalent amount 0! suliurlc acid to an ether I sulfate salt may be obtained in the same manner.

trample 5.-- p-Prperidino-s-msthylethyl bencmnirul ether 49.4 g. of benshydryl bromide is added slowly to a refluxing solution oi 00 g. of

andmostah this exampleis usedinap-.-

p-piperidino-isoescapes propanol in 150 cc. of xylene and the mixture refiuxed for about twenty hours, cooled and the lower layer consisting of the hydrobromide salt of the fi-piperidlno-isopropanol drawn off. The xylene is removed from the upper layer by distillation and the residue distilled in vacuo to obtain the free base of the desired p-piperidino-amethylethyl benzhydryl ether.

The free base can be converted to the hydrochloride selt by dissolving it in dry ether and adding an excess of dry isopropanolic hydrogen chloride. The salt which separates as a white solid is collected and purified by recrystallization from isopropanolether or isopropanol-ethyl acetate mixture.

Example 6.y-Piperidinopropyl benzhydryl ether Hal.) Ha

C B: c icon:

e residue distilled under reduced pressure to u t l! the desired y-pipericlinopropyl benzhydryl other as a colorless oil. The hydrobromide salt at this as cund can be prepared by dissolving the free base in small amount of isopropancl adding an excess of isopropanolic hydrogen bl omide.

obtain the desired hydrobomide salt as a White crystalline solid. This salt can be purified by crystallization from isopropanol-ethyl acetate .ixture.

Example ?.,8-Morphclino-a-methylethzll benzhydryl ether A mixture consisting of '75 g. of fl-morpholinoisopropanol and 16.5 g. of anhydrous potassium carbonate is heated at 125 C. while 29.5 g. of benzhydryl bromide is added slowly. After the addition has been completed the mixture is stirred and heated for about fifteen hours and then the excess amino alcohol removed by distillation in vacuo. The residue is washed with water and then added to a warm isopropanolsolution cont ning an equivalent amount of oxalic acid dihydrate. The acid oxalate salt of the desired c niorpholino a methylethyl benzhydryl ether which separates is collected, suspended in water and treated with an excess of strong sodium hydroxide solution. The free base is extracted with ether, the ether extract dried and then treated with an excess of dry hydrogen chloride. white hydrochloride salt of B-morphollnoa-methylethyi benzhydryl other which separates from the solution is collected and purified by recrystaliiaation from isoprcpanol-ether mixture.

: her extracts are dried, the ether distilled and Ether is added and the mixture cooled 6 Example 3,- -Thiomorpholinopropyl-e'- dichloro benzhydryl ether 43.3 g. of 4,4-dichlorobenzhydryl bromide in a small amount of xylene is added slowly to a refluxlng solution of g. of -thiomorpholinopropanol in cc. of xylene and the resulting mixture refluxed for twelve hours. The mixture is cooled, treated with 250 cc. of water and'the organic layer separated. The organic layer is taken up in ether and extracted with an excess of dilute hydrochloric acid. The acidic extracts are made alkaline, extracted with ether and the combined ether extracts dried. The ether is distilled and the excess amino alcohol distilled from the residue as completely as possible under high vacuo. The residue is cooled, taken up in ether, decolorized with activated carbon and the ether solution treated with an excess of dry hydrogen chloride. The hydrochloride salt of the desired y thiomorpholinopropyi-A'sdichlorobenzhydryl ether which separates is collected and purified by crystallization from isopropanol-ether mixture.

Esample 9.-- Morpholinohex1 Z benzhydryl ether CHzC H2 the ether extracts dried and the ether distilled.

The excess amino alcohol is distilled from the residue under high vacuo and the residue, aftor solution in a small amount of warm isopropanel, .added to a warm solution of isopropanol containing an equivalent amount of oxalic acid dihydrate. The acid oxalate salt of the desired {-morpholinohexyl benzhydryl other which separates from the solution on cooling is removed, suspended in water and treated with an excess of 30% sodium hydroxide solution. The purified free base is extracted with ether, the ether extracts dried and then treated with an excess of dry hydrogen chloride. The white hyrochloride salt of f-morphollnohexyl benzhydryl ether thus obtained is collected and purified by reczyo al rm'io 1 from lsop.opa11olother mixture.

Example 10.- -Piperidino-cmethylpropyl 2- methylbenzhydryl other C Ha CHrC B:

CHOCH:CHCH2N /CH2 onion ether. removed and extracted with dilute hydrochloric acid. The acidic extracts are made alkaline. extracted with ether and the ether extracts dried. The ether is removed by distillation and the residue distilled in high vacuo to obtain the free base oi the desired y-piperidino- -methylpropyl-iI-methylbenshydryl ether. Example 11.y-Morpltolino-fifi dimeth'ulpropyl benzhydrul ether CHO-CH|-CH1N 4D a. of benzhydryl bromide is added slowly to CH1 CHiCH:

' a re'fluxin: solution or 70 g. of y-morpholino-mfidimethylpropanol in 150 cc. oi benzene and the resulting mixture refluxed for about twenty-tour hours. The mixture is cooled, treated with water and the organic layer. after dilution with ether, removed. The organic layer-is extracted with dilute hydrochloric acid, the acidic extracts made alkaline with sodium hydroxide solution and extracted with ether. The combined ether extracts are dried, the ether distilled and the residue added to a warm isopropanol solution containing an equivalent amount of oxalic acid dihydrate. The acid oxalate salt which separates is removed, suspended in water and treated with an excess of 30% sodium hydroxide solution. The alkaline solution is extracted with ether, the combined ether extracts dried and, the other solution containing the free base or 'y-morpholino- AP-dimethylpropyl benzhydryl ether treated with an excess of dry hydrogen bromide. The hydrobromide salt of y-morpholino-Ap-dimethylpropyl benzhydryl ether which separates from the solution is collected and purified by recrystallization from isopropanol-ether mixture.

sample 12'.-; Ptperidino- -methylbutul 4,0-

dimethozubenzhudryl ether v 80.! a. of 4,4'-dimethoxybenzhydryl bromide dissolved in a small amount of toluene is added slowly to a refluxing solution oi 50 a. ct l-piperidino-4-pentanol in 150 cc. of toluene and the resultin: mixture heated under reflux for about twenty hours, The reaction mixture is cooled and 200 cc. of ether and 300 cc. of water added. After thorough mixing, the organic layer is separated. extracted with dilute acid and the combined acidic extracts made alkaline with N sodium hydroxide solution. The alkaline mixture is extracted with ether, the ether extracts dried and the ether distilled. The excess amino alcohol is distilled from the residue as completely as possible under high vacuo and the residue added to a warm isopropanol solution containing one equivalent of oxalic aciddihydrate. The acid oxalate salt of the base which separates on cooling is removed, suspended in water and treated with an excess or strong sodium hydroxide solution. The purified tree base which is liberated is extracted with ether. the ether extracts dried and the ether distilled. The resid- 8 ual light yellow oil consists oi the free base of the desired -piperidino-a-methylbutyl-4,4-dimethoxybenzhydryl ether.

Some further examples of the compounds of the invention which may be prepared by application of the above described methods are:

. cn-o-cmomomcnm Q cmom cn-o-omcH-N 0m H: CHlO I (ll-Q cm omen.

CH-O-CHr- CH|N\ O Q B: CHsCs CrHsO Q omom CH.OCHCHICHQN/ O n. on, B. Q onion, ono-cmcmomcmom o CHIC r cu-o-onom cm 0 H. CH-C/HI In its broader aspects the invention includes the quaternary ammonium, as well as the acid addition, salts oi the free bases of the new basically substituted ben'zhydryl ethers. These quaternary ammonium salts are prepared by reactin: an alkyl or aralkyl halide, a dialkyl sulfate or an alkyl aryl sulionate with the free base oi the benzhydryl ethers. The quaternary'ammonium halides can also be prepared by the reaction oi an w-haloalkyl benzhydryl ether compound with an N-alkyl or N-aralkyl substituted piperidine. morpholine, thiomorpholine or pyrrolidine. Some examples oi the compounds fallin: within the scope of this phase 0! the invention are: y-benzhydryloxypropyl methyl piperipiperidinium chloride. hbenzhydryloxybexyl methyl morpholinium methosuliate and the like.

These enumerated compounds as well as others of the same type may be prepared in accordance with the methods which I have fully disclosed and claimed with reference to certain prei'erred classes of the quaternary ammonium compounds of the invention in my copending applications, Serial Nos. 640,685, 640,686 and 640,- 687, all flied January 11, 1946.

Attention is called to the fact that compounds somewhat related to those claimed herein are described and claimed in my copendina' applications as follows: Serial No. 660,406, illed April 8, 1946: Serial No. 688,424, flled Auaust 5, 1946; Se-

10 rial No. 688,425, filed August 5, 1946; Serial No. 4. A compound'of the class consisting of a free 688,426, filed August 5, 194.6; Serial No. 688,427, base, its acid addition salts, and hydrocarbon filed August 5, 1946; Serial No. 739,985, filed April halide, hydrocarbon sulfate and hydrocarbon sul- 8, 1947; Serial No. 751,984, filed June 2, 1947; fonate quaternary salts, said free base having the Serial No. 751,985, filed June 2, 1947; Serial No. formula,

780,099, filed October 15, 1947; and Serial No. 33,-

1. A compound of the class Consisting of a free 'Q 0 base, its acid addition salts, and hydrocarbon cmcfi, halide, hydrocarbon sulfate and hydrocarbon sul- 432, filed June 16, 194a. Q CECE, What I claim as my invention is:

fonate quaternary salts, said freebase having the A compound of the class consisting of a free mmmla' base, its acid addition salts, and hydrocarbon R1 halide, hydrocarbon sulfate and hydrocarbon sul- Q fonate quaternary salts, said free base having the R: CHO-CJIh-R formula onion. CH-O-CHCH N/ I o where n is an integer of 2 to 6 inclusive, R is a member of the class consisting of piperidino, mor- O m CHIC I pholino, thiomorpholino and pyrrolidino radicals and R1 and R2 are members of the class consist- A compound of t formul ing of hydrogen, halogen, lower alkyl and lower alkoxy. CH CH 2. A compound of the class consisting of a free base, its acid addition salts, and hydrocarbon CHrHOI halide, hydrocarbon sulfate and hydrocarbon sulfi,

fonate quaternary salts, said free base having the f I 7. A compound of the formula,

: cH-o-c.m.1z Q Q' O/ n-o-cnionicmcmomcno O-Hcl O 01110 2 where n is an integer of 2 to 6 inclusive and R is a member of the class consisting of piperidino, morpholino, thiomorpholino and pyrrolidino rad- A compound of the formula icals. 40

3. A compound of the class consisting of a free Q CHICK base, its acid addition salts, and hydrocarbon CH-O-CH-CH N 04301 halide, hydrocarbon sulfate and hydrocarbon sul- C g m g fonate quaternary salts, said free base having the formula,

GEORGE RIEVESCHL. J R.

Q ed nm No references c OH-O-CH-G Ha 0111C 

